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Biomedical subjects

M R Nelson

Publications and source records attributed to M R Nelson.

At least 19 recordsLinked to original sources
PubMed2003

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/

Database Management Systems↗
PubMed2003

Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness.

Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.

Anti-HIV Agents↗
PubMed2003

Restoration of human immunodeficiency virus-1-specific responses in patients changing from protease to non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

The effect of altering antiretroviral therapy (ART) on responses to viral, recall and human immunodeficiency virus (HIV)-1-specific recombinant antigens and interleukin-2 (IL-2) in HIV-1-infected patients was assessed. A longitudinal cohort study in eight HIV-1 infected individuals following a clinically indicated therapy change (seven for drug intolerance and one for virological failure) from protease inhibitor (PI) to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimens was performed. CD4 T-cell counts, viral loads, lymphoproliferative responses, cytokine production and latent proviral deoxyribonucleic acid (DNA) were measured at baseline and at weeks 12 and 24 after therapy substitution. Following therapy-switch there was a 33% proportional increase in mitogen response (95% confidence interval (CI), 3-33%) and a 31% increase (95% CI, 15-48%) in viral and recall-antigen responses. Six patients developed proliferative responses to low concentration IL-2 stimulation. All patients demonstrated an increase in median HIV-1-specific responses, as three had detectable virus at baseline (two being viral rebound); this may reflect an autovaccination effect. Proviral DNA changes largely reflected plasma HIV-1 ribonucleic acid (RNA). In conclusion, NNRTI substitution for a PI may favour immune reconstitution with an improvement in HIV-1-specific responses, which may reflect differential effects on antigen processing and presentation, an autovaccination effect or alternatively a potential suppressive effect of the PI.

Anti-HIV Agents↗
PubMed2002

Impact of NNRTI compared to PI-based highly active antiretroviral therapy on CCR5 receptor expression, beta-chemokines and IL-16 secretion in HIV-1 infection.

Interleukin-16 (IL-16) and the beta-chemokines (RANTES, monocyte chemotactic protein-1 (MCP-1), macrophage inhibitory protein (MIP)-1alpha and (MIP)-1beta) are soluble in vitro suppressors of macrophage tropic HIV-1 strains. The reduction of HIV-1 RNA plasma levels in late-stage patients receiving protease inhibitors has been associated with increased concentrations of MIP-1alpha, MIP-1beta, RANTES and IL-16 and a decrease in levels of MCP-1. We determined plasma levels of MCP-1, MIP-1alpha, MIP-1beta, RANTES and IL-16 during the first 16 weeks of highly active antiretroviral therapy (HAART) in chronic HIV-1-infected patients. Patients were administered one of two therapeutic regimens based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). No differences were seen in the levels of RANTES and IL-16 over the first 16 weeks of HAART in either treatment group. MCP-1 decreased significantly in the PI-treated group over the first 16 weeks of HAART (P = 0.0003). A significant increase was observed in the levels of MIP-1alpha and MIP-1beta in the NNRTI cohort (P = 0.0010 and P = 0.0012, respectively). A significant decrease in levels of MIP-1alpha and MIP-1beta (P = 0.0015 and P = 0.0299, respectively) was observed over the 16 weeks in the PI cohort. A significant difference was seen when the levels of MIP-1alpha and MIP-1beta were compared between the NNRTI and the PI cohorts at week 16 (P = 0.04 and P = 0.05, respectively). Evaluation of CCR5 expression ex vivo revealed no difference between the two treatment groups. Patients were genotyped for CCR5 Delta32 and the incidence of heterozygosity was lower than in the HIV-1 seronegative controls (3% compared to 19%).

Adult↗
PubMed2001

Cessation of secondary prophylaxis in patients with cryptococcosis.

Cryptococcal disease in HIV-positive individuals is usually a consequence of advanced immunosuppression. Treatment consists of long period of induction therapy followed by long-term secondary prophylaxis, usually with fluconazole. The introduction of highly active antiretroviral therapy has resulted in improvements in immunological function such that the cessation of primary and secondary prophylaxis against several opportunistic infections has become possible. We report our experience of the cessation of secondary antifungal prophylaxis in patients responding to highly active antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2001

PBS/RPBS cost implications of trends and guideline recommendations in the pharmacological management of hypertension in Australia, 1994-1998.

OBJECTIVES: To determine the extent to which "current guidelines" for the management of hypertension are reflected in the prescribing of antihypertensive drugs in Australia over the period 1994-1998, and to examine the cost implications of actual and recommended prescribing patterns. DESIGN: Federal Government and consumer cost estimates modelled on prescribing patterns and guideline recommendations over the period 1994-1998. SETTING: Prescribing on Federal Government pharmaceutical schemes over the 1994-1998 period. MAIN OUTCOME MEASURES: Estimates of Pharmaceutical Benefits Scheme/Repatriation Pharmaceutical Benefits Scheme cost changes in Australian dollar values. RESULTS: The implementation of current guidelines for patients with uncomplicated hypertension taking monotherapy alone could have reduced drug costs by $45-$108 million in 1998. CONCLUSIONS: Current prescribing patterns indicate that clinical practice has pre-empted the results from clinical trials of newer, more expensive agents and that clinicians' prescribing patterns do not closely reflect current recommendations.

Antihypertensive Agents↗
PubMed2001

Investigation and control of a large outbreak of multi-drug resistant tuberculosis at a central Lisbon hospital.

An increase in the number of new cases of tuberculosis (TB) combined with poor clinical outcome was identified among HIV-infected injecting drug users attending a large HIV unit in central Lisbon. A retrospective epidemiological and laboratory study was conducted to review all newly diagnosed cases of TB from 1995 to 1996 in the HIV unit. Results showed that from 1995 to 1996, 63% (109/173) of the Mycobacterium tuberculosis isolates from HIV-infected patients were resistant to one or more anti-tuberculosis drugs; 89% (95) of these were multidrug-resistant, i.e., resistant to at least isoniazid and rifampicin. Eighty percent of the multidrug-resistant strains (MDR) available for restriction fragment length polymorphism (RFLP) DNA fingerprinting clustered into one of two large clusters. Epidemiological data support the conclusion that the transmission of MDR-TB occurred among HIV-infected injecting drug users exposed to infectious TB cases on open wards in the HIV unit. Improved infection control measures on the HIV unit and the use of empirical therapy with six drugs once patients were suspected to have TB, reduced the incidence of MDR-TB from 42% of TB cases in 1996 to 11% in 1999.

AIDS-Related Opportunistic Infections↗
PubMed2001

A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation.

Recent advances in genome research have accelerated the process of locating candidate genes and the variable sites within them and have simplified the task of genotype measurement. The development of statistical and computational strategies to utilize information on hundreds -- soon thousands -- of variable loci to investigate the relationships between genome variation and phenotypic variation has not kept pace, particularly for quantitative traits that do not follow simple Mendelian patterns of inheritance. We present here the combinatorial partitioning method (CPM) that examines multiple genes, each containing multiple variable loci, to identify partitions of multilocus genotypes that predict interindividual variation in quantitative trait levels. We illustrate this method with an application to plasma triglyceride levels collected on 188 males, ages 20--60 yr, ascertained without regard to health status, from Rochester, Minnesota. Genotype information included measurements at 18 diallelic loci in six coronary heart disease--candidate susceptibility gene regions: APOA1--C3--A4, APOB, APOE, LDLR, LPL, and PON1. To illustrate the CPM, we evaluated all possible partitions of two-locus genotypes into two to nine partitions (approximately 10(6) evaluations). We found that many combinations of loci are involved in sets of genotypic partitions that predict triglyceride variability and that the most predictive sets show nonadditivity. These results suggest that traditional methods of building multilocus models that rely on statistically significant marginal, single-locus effects, may fail to identify combinations of loci that best predict trait variability. The CPM offers a strategy for exploring the high-dimensional genotype state space so as to predict the quantitative trait variation in the population at large that does not require the conditioning of the analysis on a prespecified genetic model.

Adult↗
PubMed2001

The management of chronic hepatitis B infection.

Chronic hepatitis B infection is frequently diagnosed within the genitourinary clinic setting with sexual transmission the commonest route of acquisition in the United Kingdom. Only 3--5% of adults who contract acute hepatitis B will progress to chronic infection, and these individuals can be identified by the presence of hepatitis B surface antigen (HBsAg) in the bloodstream 6 months after infection. Individuals at highest risk of long-term complications such as cirrhosis and hepatocellular carcinoma, carry HBeAg and have high levels of circulating hepatitis B virus (HBV) deoxyribonucleic acid (DNA). Therapy should be targeted towards this group of patients. Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine. Seroconversion occurs in 30--40% of patients treated with interferon and treatment is often limited by toxicity. Lamivudine is well tolerated with seroconversion rates of 15--20% at one year, rising with increasing duration of therapy. Long-term monotherapy is limited however by the development of resistance mutations and combination nucleoside therapy is likely to become the treatment of choice in the future. Patients with chronic hepatitis B should be counselled regarding transmission, partner vaccination and alcohol intake and co-infection with other hepatitis viruses should be excluded.

Antiviral Agents↗
PubMed2001

Effect of a statewide neonatal resuscitation training program on Apgar scores among high-risk neonates in Illinois.

OBJECTIVE: The national Neonatal Resuscitation Program (NRP), started in 1987, provided training to hospital delivery room personnel to standardize knowledge and skills to reduce neonatal morbidity and mortality and increase successful resuscitation during the first few critical minutes after birth. The Apgar score continues to be used as the best established index of immediate postnatal health. The purpose of this study was to evaluate the impact of the NRP instruction in Illinois hospitals by examining Apgar scores among high-risk infants who are likely to benefit from the NRP. METHODS: A retrospective 3-time period cohort design was used (before the introduction of the NRP, 1985-1988; transition when NRP training occurred, 1989-1990; and after NRP training was completed at least once for some delivery room personnel in each Illinois hospital, 1991-1995). Illinois computerized birth certificate files on a selected group of 636 429 high-risk neonates provided information on Apgar scores and maternal characteristics. The American Academy of Pediatrics provided instructor lists to determine when NRP training started and when it was fully implemented in Illinois. Illinois Department of Public Health provided data to categorize hospitals into levels based on type and intensity of neonatal services (Level I, II, II+, III). High-risk neonates were defined as meeting 1 of the following criteria: maternal age <20 years old or >35 years old, birth weight <2500 g or >4000 g, presence of a maternal medical risk factor, and no prenatal care or prenatal care started after the first trimester. Several exclusion criteria were applied including the following: birth records with missing data, multiple birth or congenital anomaly, and hospital information that indicate no birth deliveries in 1 of the 11 study years or delivery outside of a hospital. One-minute and 5-minute Apgar scores were divided into categories for analysis (0-3, 4-6, 7-10). No change or a decrease in a low (0-6) 1-minute Apgar when compared with the 5-minute Apgar was a primary measure to evaluate effect of NRP resuscitation. Variables examined included the following: race/ethnicity, maternal age, level of education, presence of maternal medical risk factor, trimester started prenatal care, complications of labor and delivery, and a low birth weight. Analysis consisted of chi(2) tests, relative risk calculations, and logistic regression to reveal independent associations with no change in low 1-minute Apgar score or continued low (0-6) 5-minute Apgar. RESULTS: A total of 636 429 high-risk birth records was selected for detailed analyses out of 2 077 533 births in Illinois between 1985 and 1995 for 193 hospitals. The number of active NRP instructors in Illinois changed dramatically during the study period; for example, 1 to 6 between 1987 and 1988 to 1096 to 1242 between 1991 and 1995. The percentage of neonates reported to have low (<7) 1-minute Apgar score decreased in 1991 to 1995 overall and for each of 4 hospital levels. Overall and by hospital level, there was a statistically significant lower proportion of high-risk newborns who showed a decrease or no change in their 5-minute Apgar scores after the NRP instruction. After adjusting for several maternal characteristics, logistic regression analysis revealed that high-risk newborns with a low 1-minute Apgar were more likely to increase their 5-minute Apgar after the NRP instruction in 1991 to 1995. Additional analyses indicated that very low birth weight and low birth weight newborns benefited the most from NRP instruction. CONCLUSION: Although previous research has shown that the NRP instruction improves knowledge and skill among health care personnel in the delivery room, both short-term and long-term, there has been little evidence to demonstrate NRP impact on infant morbidity. Several strategies were used in this study to control for bias and to adjust for secular trends in decreased infant morbidity during the study period. This study demonstrated sufficient support for the hypothesis that a significant improvement occurred among neonates in their Apgar score after the NRP instruction in Illinois. Empirical support is provided for the clinical effectiveness of NRP instruction.

Apgar Score↗
PubMed2000

Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy.

Clinical data on 7840 HIV-positive patients, representing 43 745 patient-years of follow-up, has been collected. All patients with ARL since 1986 (n = 150) were assessed at presentation for prognostic factors and outcomes recorded. Comparisons are made between cases in the pre-HAART era (1988-1995), and the HAART era (1996-1999). Statistical models are used to calculate the incidence of ARL and factors predicting its development. The incidence of ARL has not changed over time (3 to 7 of 1000 patients per year, P = .933), but contributes to a greater percentage of first AIDS-defining illnesses (ADI) in the HAART era (P < or = .0001). Older age, nadir CD4 count, and no prior HAART use, predict the development of ARL. There has been no change in stage at presentation, presence of B symptoms, performance status, or marrow involvement between the 2 time cohorts or between patients with or without prior HAART exposure. Similarly, there is no difference in survival duration between the pre-HAART and HAART era (log rank P = .15) or specifically in patients treated with HAART before ARL diagnosis (log rank P = .12). The use of HAART has not yet been shown to influence the incidence or survival of ARL. However, because nadir CD4 count and use of HAART are independent predictors of ARL development, this may translate into a future fall in new cases. (Blood. 2000;96:2730-2734)

Adult↗
PubMed1999

Evaluation of sperm washing as a potential method of reducing HIV transmission in HIV-discordant couples wishing to have children.

OBJECTIVE: A number of discordant couples, in whom the man is HIV positive and the woman is HIV negative, wish to have children. To conceive they must abandon protected sex, posing a risk of HIV transmission to the woman and so to the child. In such circumstances purification of spermatozoa ('sperm-washing') to inseminate the woman artificially has been proposed as a method of reducing the risk of transmission. Here we evaluate whether this does represent a true risk reduction. METHODS: Semen samples from HIV-positive patients were separated into spermatozoa, non-sperm cells (NSCs) and plasma fractions. The amount of viral RNA present in each fraction was measured and compared with the level in the peripheral blood. Each fraction was also assessed for the presence of proviral DNA. The ability of spermatozoa to be infected was assessed by evaluating for the presence of HIV receptors, i.e. CD4, CCR5 and CXCR4 on the surface of the sperm, by flow cytometry. RESULTS: A poor correlation was found between the levels of HIV in blood and semen. Within the semen the virus was restricted to the plasma and/or NSCs. All spermatozoa were negative for viral RNA or proviral DNA. Spermatozoa did not express significant levels of CD4, CCR5 or CXCR4, suggesting that they are unlikely to be major targets for HIV infection. CONCLUSIONS: These data suggest that spermatozoa are not major targets of HIV infection. Purifying spermatozoa reduced the level of HIV RNA and proviral DNA to below the detection limit of the assays irrespective of the amount of virus present in the unfractionated semen. On the basis of these data we would recommend 'sperm-washing' followed by insemination as a safer alternative to natural conception for HIV-discordant couples wishing to have children.

DNA, Viral↗
PubMed1999

ICU admission in patients infected with the human immunodeficiency virus - a multicentre survey.

We conducted a retrospective study to assess the reasons for admission to the intensive care unit, and subsequent outcome, in patients infected with the human immunodeficiency virus (HIV). Four hospitals in the south of England participated, all with specialist HIV units. Data were collected on 127 patients admitted to ICU on 133 separate occasions between June 1993 and October 1997. The mean age on admission was 38 years (range 23-60 years). Ninety-four patients (70.7%) were documented HIV-positive before admission and 36 (27%) were diagnosed HIV-positive for the first time during admission; 36.1% were admitted with Pneumocystis carinii pneumonia. Overall ICU mortality was 33%, in-hospital mortality was 56% and the eventual mortality at the end of follow-up (March 1998) was 72%. Survival was highest in those admitted with respiratory HIV-related disease or HIV-unrelated illness. Associations with poor outcome included a prior AIDS-defining illness, a CD4 cell count of less than 100 cells.ml-1 and admission secondary to sepsis.

AIDS-Related Opportunistic Infections↗
PubMed1999

Induction of HIV-1-specific T cell responses by administration of cytokines in late-stage patients receiving highly active anti-retroviral therapy.

Highly active anti-retroviral therapy (HAART) is associated with reduction in the morbidity and mortality of patients with advanced HIV-1 disease. The ability of such treatment to improve immune responses against HIV-1 and opportunistic pathogens is variable and limited. Addition of cytokine immunotherapy to this treatment may improve immune responses. IL-2 with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to HIV-1+ individuals receiving HAART with undetectable viral loads, and CD4 counts < 100 cells/microl. In one patient presenting with Mycobacterium avium complex (MAC) infection, we evaluated the effect of cytokine immunotherapy on lymphocyte phenotype; plasma viral load; proliferative responses to mitogens, recall and HIV-1 antigens; cytokine production and message in response to non-specific and specific stimuli; and natural killer (NK) cell activity. Proliferation assays were performed in two similar patients. Before cytokine immunotherapy the predominant CD8+ population was mainly CD28-. No proliferation or IL-2 production was seen in response to mitogens, recall or HIV-1 antigens; and no HIV-1 peptide-specific interferon-gamma (IFN-gamma)-secreting cells were present. Low levels of IL-4 were detected in response to antigens to which patients had been exposed, associated with up-regulated expression of costimulatory molecules influenced by IL-4. Following IL-2 administration, loss of IL-4 was associated with increased NK cell activity and HIV-1 peptide-specific and non-specific IFN-gamma-producing cells. Proliferative responses associated with IL-2 production and responsiveness were only seen after subsequent concomitant administration of GM-CSF with IL-2. These changes mirrored clinical improvement. An imbalance of lymphocyte subsets may account for immune unresponsiveness when receiving HAART. Restoration of responses following immunotherapy suggests a shift towards a lymphocyte profile with anti-pathogen activity.

Acquired Immunodeficiency Syndrome↗